The recent identification of recurrent genetic alterations in specific cancer genes has led, through biological and biochemical analyses, to new molecularly-targeted therapies for lung cancer that have shown promise in the clinic. Still, while genomic studies continue to identify lesions of potential therapeutic relevance to cancer, functional studies, which are historically slow, are required to validate these as potential targets and develop strategies to exploit them for therapeutic benefit. Among the most prominent genomic alterations occurring in NSCLC are point mutations leading to RAS oncoprotein activation, mutation and chromosomal losses involving the p53 tumor suppressor locus on chromosome 17p, and large deletions affecting the short arm of chromosome 8 (8p). These alterations have been known for many years and often occur in the same tumors, yet precisely how they contribute to lung cancer development and how they can be exploited remains unknown. The goal ofthis project is to understand the biological and mechanistic impact of KRAS, p53, and 8p alterations on the initiation and maintenance of lung cancer, and to initiate efforts to exploit their alteration for therapeutic purposes. The project's co-investigators have a history of collaboration and collective expertise in tumor suppressor genes, mouse modeling, and drug resistance mechanisms. Here they will apply genomic information obtained from human lung cancers to inform functional studies in mice, exploiting innovative technologies to characterize biological impact of known and novel lesions on lung carcinogenesis. Building on substantial preliminary data, the project will study effectors that are required for tumor maintenance in EGFR and KRAS driven lung cancers (alone and in combination with targeted drugs), explore the action of p53 in RAS limiting lung carcinoma development, and begin to characterize new genetic lesions that drive lung carcinogenesis. The project imports new mouse models and technologies into the program, and interacts with, and benefits from, each ofthe other projects and cores. Successful completion ofthe proposed work will provide a critical foundation for improving prognostic tools and developing new targeted therapeutic strategies with new agents or drug combinations.